delta-3, 20-diketo-17-hydroxy-11, 21-bis oxygenated-pregnadiene compounds and processes of preparing the same



Lewis H. Sarett, Princeton, N. J., assignor to Merck & Co., Inc.,Rahway, N. J., a corporation of New Jersey No Drawing. ApplicationJanuary 25, 1955, Serial No. 483,858

10 Claims. (Cl. 260-49745) This invention is concerned generally withnovel steroid compounds and processes of preparing them. More par-Patent 2 imide, is converted to A -3-ethylenedioxy-7-bromo-11,20-diketo-l7-hydroxy-2l-acyloxy-pregnene. This 7-bromoderivative is reactedwith collidine thereby forming A 3 ethylenedioxy 11,20diketo-17-hydroxy-2l-acyloxypregnadiene which is converted, by reactionwith an aqueous mineral acid in contact with a water-immiscible solventsuch as chloroform, to A-3,11,20-triketo-l7-hydroxy-Zl-acyloxy-pregnadiene as for example M-3,11,20- triketo l7 hydroxy 2l-a1kanoyloxy-pregnadiene, A3,11,20-triketo-l7-hydroxy-2l-acetoxy-pregnadiene, A

, 3,11,20 triketo l7-hydroxy-2l-propionoxy-pregnadiene, A3,11,20-triketo-l7-hydroxy-2l-benzoxy-pregnadiene,

ticularly, it relates to A -3,20-diketo-17-hydroxy-11,21-

bis-oxygenated-steroids of the pregnane series having an unsaturatedlinkage attached to the 0-8 carbon atoms, and with processes ofpreparing these novel C-8 unsaturated A -steroid compounds. These newC-8 unsaturated A 3,20-diketo-17-hydroxy-l1,21-bis-oxygenated-steroidspossess pharmacological activity similar to that shown by cortisone andare thus of value in the treatment of conditions which heretoforeresponded to the administration of the adrenal hormone cortisone.Moreover, in addition to possessing cortisone-activity, these new C-8unsaturated A -3,20-diketo-l7-hydroxy-l l,20-bis-oxygenatedsteroidsdifier from cortisone in being relatively free from sodium or waterretention action, and are thus especially effective in the treatment ofarthritis and related diseases, producing their cortisone action withoutproducing undesired metabolic effects such as edema.

These A -3,20-diketo-17-hydroxy-11,21-bis-oxygenatedsteroid compounds ofthe pregnane series, having an unsaturated linkage attached to the C8carbon atom, in-

clude A 3,20-diketo-17-hydroxy-11,21-bis-oxygenated pregnadienes(Compound 1 hereinbelow), A -3,20-diketo 17 hydroxy 11,21 bisoxygenated-pregnadienes (Compound 2), and A-3,20-diketo-17-hydroxy-11,21- bis-oxygenated-pregnadienes (Compound 3),which may be chemically represented as follows:

CHzOZ wherein R is a radical connected to C-ll by a carbonoxygenlinkage, and Z is hydrogen or an acyl radical.

The A 3,20 diketo-l7-hydroxy-2l-bis-oxygenatedpregnadienes are preparedby reacting A -3,ll,20-diketo 17 hydroxy-2l-acyloxy-pregnene withethylene glycol to form A5 4 3 ethylenedioxyl1,20-diketo-l7-hydroxy-21-acyloxy-pregnene which, upon reaction with -.bromsuccin,-

and the like. These A -3,11,20-triketo-l7-hydroxy-21acyloxy-pregnadienes are reacted with a hydrolyzing agent such as sodiummethoxide in methanol to produce A3,11,20-triketo-l7,2l-dihydroxy-pregnadiene.

The A 3,11,20-triketo-l7,2l-dihydroxy-pregnadiene is reacted withsemicarbazide to form A -3,11,20-triketo- 17hydroxy-2l-acyloxy-pregnadiene 3,20-bis-semicarbazone which is reactedwith an alkali metal borohydride, preferably lithium borohydride underanhydrous conditions, to produce A 3,20 diketo-11,17-dihydroxy-2lacyloxy-pregnadiene 3,20-bis-semicarbazone. The latter compound is thenreacted 'with an aqueous mineral acid solution in contact with awater-immiscible solvent such as chloroform to produce A-3,20-diketo-l1,17-dihydroxy-21-acyloxy-pregnadiene as for example N-3,20- diketo-l 1, l7-dihydroxy-2l-alkanoyloxy-pregnadiene, A 3,2Odiketo 11,17 dihydroxy 2l-acetoxy-pregnadiene, A 3,20diketo-11,l7-dihydroxy-2l-propionoxy-pregnadiene, A-3,20-diketo-11,17-dihydroxy-2l-benzoxy-prege nadiene, and the like.These A -3,20-diketo-11,17-dihydroxy-2l-acyloxy-pregnadienes are reactedwith a hydrolyzing agent such as sodium methoxide in methanol to form A-3,20-diketo-11,l7,21-trihydroxy-pregnadiene,

The A 3,20,diketo-17-hydroxy-11,21-bis-oxygenated-pregnadienes areprepared by arearrangement reaction in which a solution of A-3,11,20-triketo-17-hydroxy- 21 acyloxy-pregnadiene or A-3,20-diketo-11,17-dihydroxy-2l-acyloxy-pregnadiene, in anorganicsolvent suchpalladium catalyst thereby.

as ethyl acetate, is shaken with isomerizing the A703) double bond tothe A804) position to produce A-3,11,ZO-triketo-17-hydroxy-21-acyloxypregnadiene or A-3,20-diketo-11,17-dihydroxy-21- acyloxy-pregnadiene, as for example A-3,11,20 tri-, keto l7 hydroxy-2l-alkanoyloxy-pregnadiene, A f 3,11,20triketo 17 hydroxy 21 acetoxy-pregnadiene, A4304)3,11,20-triketo-17-hydroxy-2 l-propionoxy-preg nadiene, A-3,11,20-triketo-17-hydroxy-2l-benzoxya.

pregnadiene, M1804) 3,20-diketo-11,17-dihydroxy-21-dikanoyloxypregnadiene,

dihydroxy 21 ated pregnadienes are conveiently prepared starting with,the known A -9-bromo-cortisone. The A -9-bromo-corti-.

sone is reacted with a dehydrohalogenating agent such as collidine toproduce A 3,11,20 triketo 17,21 di-' hydroxy-pregnadiene which can bereacted with an acylating agent, if desired, to produce thecorresponding A 3,11,20 triketo -117 hydroxy 21 acyloxy-j pregnadiene.The xv 3,11,20 triketo 17,21 di- A -3 ,20-diketo-11,17-dihy-- droxy-2l-acetoxy-pregnadiene, A -3,20-diketo-1 1,17 propionoxy-pregnadiene, A-3,20-di-, keto-11,17-dihydroxy-2l-benzoxy pregnadiene, and the with ahydrolyzing agent, these.

triketo 17 hydroxy 21 acyloxy pregnadiene) is reacted with semicarbazideto form the corresponding 3,20-bis-semicarbazone which, upon reactionwith an alkali metal borohydride, such as sodium borohydride in aqueoustetrahydrofurau, is converted to A 3,20- diketo 11,17,21 trihydroxypregnadiene 3,20 bissemicarbazone. The latter compound is then reactedwith an aqueous mineral acid solution in contact with a water-immisciblesolvent such as chloroform to produce A430?) 3,20 diketo 11,17,21trihydroxy pregnadiene, which is reacted with an acylating agent as forexample a lower alkanoic anhydride, such as acetic anhydride, propionicanhydride or butyric anhydride, benzoic anhydride, and the like, in thepresence of a tertiary amine such as pyridine to form A459) 3,20 diketo-11,17 dihydroxy 21 acyloxy pregnadiene as for example A 3,20 diketo11,17 dihydroxy 21- acetoxy pregnadieue, M 3,20 diketo 11,17 dihydroxy21 propionoxy pregnadiene, A 3,20- diketo 11,17 dihydroxy 21 butyroxypregnadiene, A 3,20 diketo 11,17 dihydroxy 21 benzoxypregnadiene, andthe like.

The following examples illustrate methods of carrying out the presentinvention but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

Example 1 To a mixture of 25 parts of dry benzene and 1.95 parts ofethylene glycol is added 0.46 part of A -3,11,20- triketo l7 hydroxy 21acetoxy pregnene and 0.03 part of p-tolueue sulfonic acid monohydrate.This solution is heated under reflux for about 20 hours during whichtime the water formed by the reaction is removed by azeopropicdistillation. The reaction mixture is cooled to room temperature and theacid catalyst is neutralized by the addition of 0.06 part of pyridine.The benzene solution is washed with 25 parts of water, and the waterwash is reextracted twice with ether. The combined benzene and etherextracts are washed with water, with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered, and the solventsevaporated in vacuo. The residual material is purified byrecrystallization from ether-petroleum-ether, following achromatographic purification step if desired, to give A 3 ethylenedioxy11,20 diketo 17 hydroxy 21- acetoxy-pregnene.

A solution of 3.60 parts of A -3-ethylenedioxy-1L20- diketo l7 hydroxy21 acetoxy pregnene is dissolved in carbon tetrachloride, 1.87 parts ofN-bromosuccinimide is added, and the resulting mixture is heated underreflux for a period of approximately 20 minutes while illuminating themixture with a photo-flood light. At the end of this period, thephoto-chemical reaction is interrupted, the reaction solution is cooled,and the cold solution is filtered to remove insoluble succinimide. Thefiltered solution is then evaporated in vacuo, methanol is added to theresidual material, and the crystalline material is recovered from theslurry by filtration and purified by recrystallization from methanol(including a chromatographic purification over alumina if desired) togive substantially pure A -3-ethylenedioxy-7-bromo-11, 20 diketo 17hydroxy 21 acetoxy-pregnene.

1.7 parts of A -3-ethylenedioxy-7-bromo-11,20-diketo-17-hydroxy-2l-acetoxy-pregnene is mixed with 10 parts ofdimethylaniline, and the mixture is heated at about 90 C. for a periodof about 2 hours. The reaction mixture is diluted with 100 parts ofpetroleum ether and 50 parts of benzene, and the resulting solution iswashed successively with l N aqueous sulfuric acid, water, saturatedaqueous sodium bicarbonate solution, and finally with water. The Washedorganic layer is dried, and the dried solution is evaporated in vacuo togive crude material which is purified by chromatography over acidwashedalumina to give substantially pure M d-ethylene- 4 dioxy 11,20 diketo 17hydroxy 21 acetoxypregnadiene.

A solution of one part of A -3-ethylenedioxy-11,20- diketo 17 hydroxy 21acetoxy pregnadiene in 2.6 parts of glacial acetic acid and 1 part ofwater is heated on the steam bath for 30 minutes. The resulting mixtureis diluted with 25 parts of water, cooled, and the crude material whichseparates is extracted with ethyl acetate. The ethyl acetate extractsare washed with saturated aqueous sodium chloride solution, with 5%aqueous sodium bicarbonate solution and then with water. The ethylacetate extract is dried, filtered and the solvent evaporated in vacuo.The residual material is chromatographed over alumina and recrystallizedfrom acetone to give substantially pure A -3,11,20-triketo-17-hydroxy-21-acetoxy-pregnadiene.

One part of A -3,11,ZO-triketo-17-hydroxy-17-acetoxy-pregnadiene isdissolved in methanol containing one molecular equivalent of sodiummethoxide, and the resulting solution is allowed to stand at roomtemperature for about 10 minutes. The hydrolysis reaction solution isdiluted with water, and the precipitated material is recovered byfiltration, dried, and purified by recrystallization from a mixture ofethyl acetate and ether to give substantially pure M-3,11,20-triketo-17,21-dihydroxypregnadiene.

Example 2 One part of M-3,11,ZO-triketo-17-hydroxy-21-acetoxypregnadiene is dissolved in 200parts of ethyl acetate, one part of palladium catalyst is added to thesolution, and the resulting suspension is shaken at room temperature forabout 6 hours. The reaction mixture is filtered and the filtrate isevaporated to dryness in vacuo. The residual material is chromatographedover acid-washed alumina to give substantially pure A-3J1,20-triketo-17-hydroxy- ZI-acetoXy-pregnadiene.

One part of fi -3,11,20-triketo-l7-hydroxy-2l-acetoxy-pregnadiene isdissolved in methanol containing one molecular equivalent of sodiummethoxide, and the resulting solution is allowed to stand at roomtemperature for about 10 minutes. The hydrolysis reaction solution isdiluted with water, and the precipitated material is recovered byfiltration, dried, and purified by recrystallization from a mixture ofethyl acetate and ether to give substantially pure A-3,1l,ZO-triketo-17,21-dihydroxy-pregnadiene.

Example 3 A mixture of 0.5 part of A-3,ll,20-triketo-l7,21-dihydroxy-pregnadiene, 0.5 part of anhydroussodium acetate, 0.62 part of semicarbazide hydrochloride and 35 parts ofethanol is heated at a temperature of about 70 C. for about 3 hours. Thereaction mixture is evaporated to small volume in vacuo, theconcentrated solution is diluted with water, and the insoluble materialwhich precipitates is recovered by filtration, washed with water anddried. The resulting material is acetylated and the resulting product ispurified by recrystallization from alcohol to give substantially pure A-3,11,20-triketo-17-hydroxy-Zl-acetoxy-pregnadiene3,20-bis-semicarbazone.

To a suspension of 0.2 part of lithium borohydride in 10 parts ofanhydrous tetrahydrofuran is added, dropwise with stirring over a30-minute period, a solution of 0.44 part of M-3,11,20-triketo-l7-hydroxy-2l-acetoxy-pregnadiene3,20-bis-semicarbazone in 2.5 parts of dimethylformamide and 5 parts oftetrahydrofuran, while maintaining the reaction mixture at a temperatureof about 25 C. The resulting mixture is stirred for an additional 40minutes at 25 C., 20 parts of a 10% aqueous solution of acetic acid isadded cautiously to the mixture thereby decomposing excess lithiumborohydride. The clear solution is evaporated in vacuo nearly todryness, the residual material is slurried with 10 parts of water, andthe insoluble material is recovered by filtration, washed with water,and

5 dried to give [1 -3 ,20-diketo-11,17-dihydroxy-2l-acetoxypregnadiene3,20-bis-semicarbazone.

A mixture of 0.3 part of A-3,20-diketo-11,17-dihydroxy-Z1-acetoxy-pregnadiene3,20-bis-semicarbazone, parts of glacial acetic acid, 1.5 parts ofwater, 0.85 part of sodium acetate, and 0.8 part of 90% aqueous pyruvicacid is heated under nitrogen for 4 hours at about 75 C. The reactionmixture is diluted with 20 parts of water, and the aqueous mixture isevaporated nearly to dryness in vacuo. The residual material is slurriedwith water, and the organic material is extracted with ethyl acetate.The ethyl acetate solution is washed until neutral, dried, decolorized,and evaporated to small volume. Upon cooling the resulting concentrate,a crystalline material separates which is recovered by filtration andpurified by chromatography followed by recrystallization from ethylacetate to give substantially pure A -3,20-diketo-11,17-dihydroxy-21-acetoxy-pregnadiene.

One part of A -3,20-diketo-11,17-dihydroxy-21-acetoxy-pregnadiene isdissolved in methanol containing one molecular equivalent of sodiummethoxide, and the resulting solution is allowed to stand at roomtemperature for about minutes. The hydrolysis reaction solution isdiluted with water, and the precipitated material is recovered byfiltration, dried, and purified by recrystallization from a mixture ofethyl acetate and ether to give substantially pure A -3,20-diketo-11,17,21-trihydroxy-pregnadiene.

Example 4 One part of A-3,20-diketo-11,17-dihydroxy-21-acetoxy-pregnadiene is dissolved in 200parts of ethyl acetate, one part of palladium catalyst is added to thesolution, and the resulting suspension is shaken at room temperature forabout 6 hours. The reaction mixture is filtered and the filtrate isevaporated to dryness in vacuo. The residual material is chromatographedover acid-washed alumina to give substantially pure A-3,20-diketo-11,17-dihydroxy-2l-acetoxy-pregnadiene.

This A -3,20-diketo 11,17 dihydroxy-Zl-acetoxypregnadiene is hydrolyzedby reaction with sodium methoxide in methanol to form A-3,20-diketo-11,17,21-trihydroxy-pregnadiene.

Example 5 A solution of 3 parts of A -9-bromo-3,l1,20-triketo-17,21-dihydroxy-pregnene (9-bromo-cortisone) in 50 parts of collidine isheated for one hour under reflux, and the collidine is evaporated invacuo. The residual material is dissolved in chloroform, and thechloroform extract is washed with dilute aqueous hydrochloric acid, thenwith water, dried, and evaporated to dryness in vacuo. The residualmaterial is purified by chromatography followed by recrystallizationfrom ethyl acetate to give vA 3,11,20-triketo-17,2l-dihydroxy-pregnadiene.

A mixture of 0.5 part of A -3,l1,20-triketo-17,2l-dihydroxy-pregnadiene,0.5 part of anhydrous sodium acetate, 0.62 part of semicarbazidehydrochloride and 35 parts of 95% ethanol is heated at a temperature ofabout 70 C. for about 3 hours. The reaction mixture is evaporated tosmall volume in vacuo, the concentrated solution is diluted with water,and the insoluble material which precipitates is recovered byfiltration, washed with water and dried. The resulting material ispurified by chromatography followed by recrystallization from alcohol togive A -3,11,20 triketo-17,2l-dihydroxy-pregnadiene3,20-bis-semicarbazone.

To a suspension of 0.2 part of lithium borohydride in 10 parts ofanhydrous tetrahydrofuran is added, dropwise with stirring over a30-minute period, a solution of 0.44 part of A-3,1l,20-triketo-17,2l-dihydroxy-pregnadiene 3,20-bis-semicarbazone in2.5 parts of dimethylformamide and 5 parts of tetrahydrofuran, whilemaintaining the reaction mixture at a temperature of about 25 C. Theresulting mixture is stirred for an additional 40 minutes at 25 C., 20parts of a 10% aqueous solution of acetic acid is added cautiously tothe mixture thereby decomposing excess lithium borohydride. The clearsolution is evaporated in vacuo nearly to dryness, the residual materialis slurried with 10 parts of water, and the insoluble material isrecovered by filtration, washed with water, and dried to give A-3,20-diketo- 11,17,21trihydroxy-pregnadiene 3,20-bis-semicarbazone.

A mixture of 0.3 part of A -3,20-diketo-11,17,21- trihydroxy-pregnadiene3,20-bis-semicarbazone, 5 parts of glacial acetic acid, 1.5 parts ofwater, 0.85 part of sodium acetate, and 0.8 part of 90% aqueous pyruvicacid is heated under nitrogen for 4 hours at about C. The reactionmixture is diluted with 20 parts of water, and the aqueous mixture isevaporated nearly to dryness in vacuo. The residual material is slurriedwith water, and the organic material is extracted with ethyl acetate.The ethyl acetate solution is washed until neutral, dried, decolorized,and evaporated to dryness. The residual material is purified bychromatography followed by recrystallization from ethyl acetate-ether togive A -3,20-diketo-l1,17,21-trihydroxy-pregnadiene. The latter materialis reacted with an excess of acetic anhydride in pyridine at roomtemperature for a period of about 15 hours, and the crude acetylatedproduct is purified by chromatography followed by recrystallization fromethyl acetate to give substantially pure A -3,20-diketo-1l,17-dihydroxy-2l-acetoxy-pregnadiene.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of this invention.

I claim:

1. A A 3,20 diketo 17 hydroxy 11,21 bisoxygenated-pregnadiene selectedfrom the group which consists of A-3,11,ZO-triketo-17,21-dihydroxy-pregnadiene, A4304) 3,20diketo-11,17,21-trihydroxy-pregnadiene, and 21-lower alkanoyl estersthereof.

2. M 3,11,20 triketo-17-hydroxy-21-lower alkanoyloxy-pregnadiene.

3. 51-13(14) 3,11,20 triketo 17 hydroxy 21 acetoxy-pregnadiene.

4. A4'8(14) 3,11,20 triketo 17,21 dihydroxy pregnadiene.

5. M 3,20 diketo 11,17 dihydroxy 21 lower alkanoyloxy-pregnadiene.

6. A 3,20 diketo 11,17 dihydroxy 21 acetoxy-pregnadiene.

7. M1304) 3,20 diketo 11,17,21 trihydroxy pregnadiene.

8. The process which comprises reacting M -3,11,20- triketo17-hydroxy-21-(lower alkanoyloxy)-pregnadiene with palladium catalyst inthe presence of an organic solvent to produce A-3,11,20-triketo-17-hydroxy-2l (lower alkanoyloxy) -pregnadiene.

9. The process which comprises reacting A -3,20-diketo11,17-dihydroxy-21-(lower alkanoyloxy)-pregnadiene with palladiumcatalyst in the presence of an organic solvent to produce A-3,20-diketo-11,17-dihydroxy- 21- (lower alkanoyloxy) -pregnadiene.

10. The process which comprises reacting a (A -3,20-diketo-17-hydroxy-11,21-bis-oxygenated-pregnadiene with palladiumcatalyst in the presence of an organic solvent, thereby isomerizing theA double bond to the A804) position to produce the corresponding A-3,20-diketo- 17-hydroxy-1 1,21-bis-oxygenated-pregnadiene.

References Cited in the file of this patent UNITED STATES PATENTS2,409,798 Reichstein Oct. 22, 1946 2,689,856 Miescher Sept. 21, 1954

1. A$4,8(14)-3,20- DIKETO-17-HYDROXY-11,21-BISOXYGENATED-PREGNADIENESELECTED FROM THE GROUP WHICH CONSISTS OF$4,3(14)-3,11,20-TRIKETO-17,21-DIHYDROXY-PREGNADIENE, $4,8(14)- 3,20DIKETO-11,17,21-TRIHYDROXY-PREGNADIENE, AND 21-LOWER ALKANOYL ESTERSTHEREOF..